Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally and in the United States. More than half of COPD patients have emphysema on computed tomography, which is associated with increased mortality, but medical therapies for COPD exclusively target the airways. The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited 327 participants to test the endothelial hypothesis of emphysema, which posits that smoking-related pulmonary endothelial damage contributes to emphysema. The MESA COPD Study confirmed its primary aims that: pulmonary microvascular blood flow (PMBF) on magnetic resonance imaging (MRI) is substantially reduced COPD and emphysema of all severities; endothelial microparticles are increased and endothelial progenitor cells are reduced; and gene expression in peripheral blood mononuclear cells is strongly linked to PMBF. Although supportive of the endothelial hypothesis, findings also may be due to newly described aberrant hypoxic pulmonary vasoconstriction (HPV) or residual HPV from impaired ventilation. We also found that right ventricular (RV) volumes were reduced in COPD and emphysema, a condition we have termed cor pulmonale parvus. This condition is associated with all-cause mortality in the general population and might result, pilot data suggest, from RV stiffness and subtle ventilatory impairment. The renewal is a longitudinal continuation of the MESA COPD Study in which we aim to use regional measures of oxygen tension, ventilation, PMBF and emphysema, along with interventions to reverse HPV and to treat hyperinflation, and innovative measures of RV function and venous blood flow on MRI to test the hypotheses that: emphysema is characterized by reduced PMBF independent of HPV and ventilatory impairment; cor pulmonale parvus is associated with RV stiffness and increased intrathoracic pressure; and reduced PMBF in non-emphysematous regions of the lung is associated with the local development of emphysema and tissue loss at five years. Innovative aspects of this proposal include the use of novel MRI imaging modalities of direct clinical relevance, examination of a new entity, cor pulmonale parvus, and the longitudinal testing of the vascular hypothesis of emphysema in humans. Confirmation of these aims would create a paradigm shift in COPD treatment to justify the testing of existing and novel (e.g., EPC/stem cell) therapies targeted to the pulmonary vasculature in emphysema, provide a potential imaging biomarker to facilitate early phase, short-term clinical trials of such therapies, and suggest mechanisms to approach and possibly treat cor pulmonale parvus.